RESUMEN
Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases that currently includes some 130 different types. CDG diagnosis is a challenge, not only because of this large number but also because of the huge clinical heterogeneity even within a number of CDG. In addition, the classical screening test, serum transferrin isoelectrofocusing, is only positive in about 60% of CDG, and can even become negative in some CDG particularly in PMM2-CDG, the most frequent N-glycosylation defect. In order to facilitate CDG diagnosis, we hereby provide some practical tools: (1) a list of clinical features strongly suggestive of a distinctive CDG; (2) a table of clinical, biochemical and laboratory findings reported in CDG, arranged per organ/system; (3) an overview of the affected organs/systems in each CDG; and (4) a diagnostic decision tree in face of a patient with a suspicion of CDG. Most important is to keep in mind a CDG in any unexplained syndrome, in particular when there is neurological involvement. This mini-review enumerates clinical and biochemical hallmarks of these diseases and the biochemical and genetic testing available, and provides an updated list and information on identified CDG. The main aim is to act as a CDG diagnosis simplified guide for healthcare professionals and, additionally, as an awareness and lobbying tool to help in the effectiveness and promptness of CDG diagnosis.
Asunto(s)
Trastornos Congénitos de Glicosilación/diagnóstico , Pruebas Genéticas , Trastornos Congénitos de Glicosilación/patología , Glicosilación , Humanos , Mutación , Secuenciación del ExomaRESUMEN
Protein misfolding has been linked to numerous inherited diseases. Loss- and gain-of-function mutations (common features of genetic diseases) may cause the destabilization of proteins, leading to alterations in their properties and/or cellular location, resulting in their incorrect functioning. Misfolded proteins can, however, be rescued via the use of proteostasis regulators and/or pharmacological chaperones, suggesting that treatments with small molecules might be developed for a range of genetic diseases. This work describes the potential of these small molecules in this respect, including for the treatment of congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG).
Asunto(s)
Deficiencias en la Proteostasis/tratamiento farmacológico , Deficiencias en la Proteostasis/etiología , Animales , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Predisposición Genética a la Enfermedad , Glicosilación/efectos de los fármacos , Humanos , Mitocondrias , Mutación , Deficiencias en la Proteostasis/diagnóstico , Deficiencias en la Proteostasis/metabolismoRESUMEN
AIM: To evaluate the effects of a long period of oestrogen deficiency on the development of apical periodontitis in rats. METHODOLOGY: Wistar rats (n = 24), 3 months old, evaluated by vaginal cytology, were included in the study. Twelve animals were ovariectomized (OVX group) and the other 12 were sham operated (control group). One hundred and twenty days after castration, the pulps of the left mandibular first molars were exposed to induce the development of apical periodontitis. Body mass was verified on a weekly basis. Following 21 and 40 days of lesion induction, the animals were sacrificed. Blood was collected for biochemical analysis, and mandibles were removed for radiographic analysis. Comparative analysis of the data was performed by the nonparametric Kruskal-Wallis and Dunn's multiple-comparisons tests. The t-test was applied to compare the oestrogen levels between control and OVX groups. RESULTS: Radiographs revealed that apical periodontitis lesions were significantly larger in the 40-day OVX group when compared with both 40-day (P < 0.05) and 21-day (P < 0.001) control groups. Serum oestrogen levels were significantly lower in the OVX group (P < 0.01), confirming the efficacy of castration. Oestrogen deficiency resulted in significantly greater body mass gain (P < 0.01) in 40-day OVX group when compared with 40-day control group. Serum concentrations of calcium were similar between groups (P > 0.05). Alkaline phosphatase levels, although higher in the OVX groups (21 and 40 days), were not significantly different. CONCLUSIONS: Ovariectomized rats had significantly larger apical periodontitis lesions after 40 days of pulp exposure when compared with controls. These findings suggest that bone alterations as a result of long periods of oestrogen deficiency can influence the progression of apical periodontitis.
Asunto(s)
Estrógenos/deficiencia , Periodontitis Periapical/etiología , Animales , Femenino , Ovariectomía , Ratas , Ratas WistarRESUMEN
Specific mitochondrial enzymatic deficiencies in the catabolism of branched-chain amino acids cause methylmalonic aciduria (MMA), propionic acidemia (PA) and maple syrup urine disease (MSUD). Disease-causing mutations were identified in nine unrelated branched-chain organic acidurias (BCOA) patients. We detected eight previously described mutations: p.Asn219Tyr, p.Arg369His p.Val553Glyfs*17 in MUT, p.Thr198Serfs*6 in MMAA, p.Ile144_Leu181del in PCCB, p.Gly288Valfs*11, p.Tyr438Asn in BCKDHA and p.Ala137Val in BCKDHB gene. Interestingly, we identified seven novel genetic variants: p.Leu549Pro, p.Glu564*, p.Leu641Pro in MUT, p.Tyr206Cys in PCCB, p.His194Arg, p.Val298Met in BCKDHA and p.Glu286_Met290del in BCKDHB gene. In silico and/or eukaryotic expression studies confirmed pathogenic effect of all novel genetic variants. Aberrant enzymes p.Leu549Pro MUT, p.Leu641Pro MUT and p.Tyr206Cys PCCB did not show residual activity in activity assays. In addition, activity of MUT enzymes was not rescued in the presence of vitamin B12 precursor in vitro which was in accordance with non-responsiveness or partial responsiveness of patients to vitamin B12 therapy. Our study brings the first molecular genetic data and detailed phenotypic characteristics for MMA, PA and MSUD patients for Serbia and the whole South-Eastern European region. Therefore, our study contributes to the better understanding of molecular landscape of BCOA in Europe and to general knowledge on genotype-phenotype correlation for these rare diseases.
Asunto(s)
3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/genética , Errores Innatos del Metabolismo de los Aminoácidos/genética , Enfermedad de la Orina de Jarabe de Arce/genética , Metilmalonil-CoA Descarboxilasa/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Acidemia Propiónica/genética , 3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/química , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Aminoácidos de Cadena Ramificada/genética , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Enfermedad de la Orina de Jarabe de Arce/fisiopatología , Metilmalonil-CoA Descarboxilasa/química , Proteínas de Transporte de Membrana Mitocondrial/química , Mutación , Fenotipo , Acidemia Propiónica/fisiopatología , Conformación ProteicaRESUMEN
Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene, which codes for the enzyme adenosine triphosphate (ATP): cobalamin adenosyltransferase (ATR). This study reports differences in the metabolic and disease outcomes of two pairs of siblings with MMA cblB type, respectively harbouring the novel changes p.His183Leu/p.Arg190dup (P1 and P2) and the previously described mutations p.Ile96Thr/p.Ser174fs (P3 and P4). Expression analysis showed p.His183Leu and p.Arg190dup to be destabilizing mutations. Both were associated with reduced ATR stability and a shorter half-life than wild-type ATR. Analysis of several parameters related to oxidative stress and mitochondrial function showed an increase in reactive oxygen species (ROS) content, a decrease in mitochondrial respiration and changes in mitochondria morphology and structure in patient-derived fibroblasts compared to control cells. The impairment in energy production and the presence of oxidative stress and fission of the mitochondrial reticulum suggested mitochondrial dysfunction in cblB patients' fibroblasts. The recovery of mitochondrial function should be a goal in efforts to improve the clinical outcome of MMA cblB type.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Alelos , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Sustitución de Aminoácidos , Fibroblastos/metabolismo , Humanos , Espacio Intracelular/metabolismo , Mitocondrias/ultraestructura , Evaluación de Resultado en la Atención de Salud , Estrés Oxidativo/genética , Especies Reactivas de Oxígeno/metabolismo , HermanosAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Mutación , Proteínas Proto-Oncogénicas c-cbl/genética , Transferasas/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transferasas Alquil y Aril , Errores Innatos del Metabolismo de los Aminoácidos/genética , Sitios de Unión , Supervivencia Celular , ADN Complementario/metabolismo , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Humanos , Chaperonas Moleculares , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Transferasas/metabolismoRESUMEN
BACKGROUND: Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most common CDG is phosphomannomutase 2 (PMM2)-CDG which often has a severe clinical presentation and life-limiting consequences. There are no approved therapies for this condition. Also, there are no validated disease-specific quality of life (QoL) scales to assess the heterogeneous clinical burden of PMM2-CDG which presents a challenge for the assessment of the disease severity and the impact of a certain treatment on the course of the disease. AIM AND METHODS: This study aimed to identify the most impactful clinical signs and symptoms of PMM2-CDG, and specific patient and observer reported outcome measures (PROMs and ObsROMs, respectively) that can adequately measure such impact on patients' QoL. The most burdensome signs and symptoms were identified through input from the CDG community using a survey targeting PMM2-CDG families and experts, followed by family interviews to understand the real burden of these symptoms in daily life. The list of signs and symptoms was then verified and refined by patient representatives and medical experts in the field. Finally, a literature search for PROMs and ObsROMs used in other rare or common diseases with similar signs and symptoms to those of PMM2-CDG was performed. RESULTS: Twenty-four signs/symptoms were identified as the most impactful throughout PMM2-CDG patients' lifetime. We found 239 articles that included tools to measure those community-selected PMM2-CDG symptoms. Among them, we identified 80 QoL scales that address those signs and symptoms and, subsequently, their psychometric quality was analysed. These scales could be applied directly to the PMM2-CDG population or adapted to create the first PMM2-CDG-specific QoL questionnaire. CONCLUSION: Identifying the impactful clinical manifestations of PMM2-CDG, along with the collection of PROMs/ObsROMs assessing QoL using a creative and community-centric methodology are the first step towards the development of a new, tailored, and specific PMM2-CDG QoL questionnaire. These findings can be used to fill a gap in PMM2-CDG clinical development. Importantly, this methodology is transferable to other CDG and rare diseases with multiple signs and symptoms.
Asunto(s)
Trastornos Congénitos de Glicosilación , Fosfotransferasas (Fosfomutasas) , Humanos , Trastornos Congénitos de Glicosilación/tratamiento farmacológico , Calidad de Vida , Glicosilación , Fosfotransferasas (Fosfomutasas)/genética , Medición de Resultados Informados por el PacienteRESUMEN
OBJECTIVES: To the best of our knowledge, no study has analyzed the association between cigarette smoking and prostate basal cell proliferation. Therefore, we sought to evaluate whether smoking status is associated with the presence of basal cell hyperplasia (BCH). METHODS: We performed a retrospective analysis of 8,196 men aged 50 to 75 years with prostate-specific antigen values between 2.5 µg/mL and 10 µg/mL and prior negative biopsy who were enrolled in the (REDUCE) trial. Cigarette smoking status was divided into current, former, or never categories at enrollment. The association between smoking and baseline BCH was evaluated, with logistic regression in univariable and multivariable analysis. RESULTS: A total of 1,233 (15.1%) men were current smokers, 3,206 (39.1%) were former smokers, and 3,575 (45.8%) were never smokers. In univariable analysis, current smoking was associated with higher baseline BCH occurrence compared with never (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.14-3.10) and former smokers (OR, 1.77; 95% CI, 1.06-2.95). Similar results were found after adjusting for patient characteristics (current vs never smokers: OR, 1.92; 95% CI, 1.14-3.26; current vs former smokers: OR, 1.71; 95% CI, 1.01-2.91). CONCLUSIONS: Among men undergoing prostate biopsy, all of whom had a negative biopsy result, current smoking at enrollment was independently associated with BCH in standard peripheral zone prostate biopsies.
Asunto(s)
Fumar Cigarrillos/efectos adversos , Hiperplasia Prostática/patología , Anciano , Animales , Biopsia , Humanos , Hiperplasia/etiología , Hiperplasia/patología , Masculino , Persona de Mediana Edad , Próstata/patología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Two human induced pluripotent stem cell (iPSC) lines were generated from fibroblasts of two siblings with methylmalonic acidemia cblB type carrying mutations in the MMAB gene: c.287TâC (p.Ile96Thr) and a splicing loss-of-function variant c.584GâA affecting the last nucleotide of exon 7 in MMAB (p.Ser174Cysfs*23). Reprogramming factors OCT3/4, SOX2, KLF4 and c-MYC were delivered using a non-integrative method based on the Sendai virus. Once established, iPSCs have shown full pluripotency, differentiation capacity and genetic stability.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Técnicas de Reprogramación Celular , Células Madre Pluripotentes Inducidas , Mutación Missense , Factores de Transcripción , Transferasas Alquil y Aril/genética , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/patología , Sustitución de Aminoácidos , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Factor 4 Similar a Kruppel , Masculino , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
This video provides a case report of a 3 year old girl with epispadia and the highlights of the surgery. A cystoscopic guided bladder neck plication was performed to achieve continence. Key points include: (1) Skin incision planning; (2) Cutaneous flap liberation to create a new urethra; (3) Complete bladder neck release to allow a controlled plication; (4) Use of cystoscopy to achieve the ideal bladder neck closure; (5) Bladder neck manipulation to achieve continence.
Asunto(s)
Epispadias/cirugía , Uretra/cirugía , Vejiga Urinaria/cirugía , Incontinencia Urinaria/cirugía , Micción/fisiología , Procedimientos Quirúrgicos Urológicos/métodos , Preescolar , Cistoscopía , Epispadias/complicaciones , Epispadias/diagnóstico , Femenino , Humanos , Incontinencia Urinaria/etiologíaRESUMEN
PURPOSE: To analyze the clinical, laboratory and pathological aspects of 20 cases of infectious endocarditis (IE) who died. The authors compared patients with diagnosis before death of IE and those with diagnosis was made after autopsy. METHODS: Twenty patients who died with IE between April 1982 and November 1991 were studied. We looked for the clinical aspects (fever, cardiac murmurs, anemia, splenomegaly, embolic events and skin manifestation), laboratory aspects (hemocultures), echocardiographic and anatomopathologic features (valvar vegetations events and embolic accidents founded at autopsy). The sample was divided in two sub-groups: A--with clinical diagnosis of IE before and B--without diagnosis before death. RESULTS: Group A--9 patients aged 8-58 years, 3 men, all them with cardiac murmurs, fever and anemia, 5 with splenomegaly. Hemocultures were done in 7 patients and positive in 1. Echocardiogram with valvar vegetation were found in 4 out of 5 patients (80% positive). At autopsy mitral valve vegetation were present in 7, aortic 3, tricuspid 3. One patient showed the exposure of three valves and two of 2 valves. Embolic events were found in 4. Group B--11 patients most of them older then 50 years (54.5%) (p < 0.05) 5 men, all them presented fever and anemia. Cardiac murmurs in 6 (54%) and none with splenomegaly. In one case hemoculture and echocardiogram, were done and were negative. Anatopathologic study showed compromise of mitral valve in 5, aortic 4, tricuspid 2, pulmonary 1. Two patients had 2 valves compromised. In one case a mural vegetation (right atrium) was found. Embolic events were present in 2 cases. CONCLUSION: In group B a significant number of patients (p < 0.05) were older than 50 years and presented his symptoms as an acute illness. We concluded that older patients with compromised general state and fever with or without embolic events IE must be remember.